Positive allosteric AMPA receptor modulators

ABSTRACT

The present invention relates to new positive allosteric AMPA receptor modulators of general formula (I)  
                 
 
     wherein R 1 , R 2  R 3 , R 4 , R 5  and R 6  may have the meanings indicated in the specification and claims, processes for preparing them and their use as pharmaceutical compositions.

FIELD OF THE INVENTION

[0001] The present invention relates to novel compounds that arepositive allosteric AMPA receptor modulators, processes for preparingthem and their use, as pharmaceutical compositions, in the treatment ofvarious disease conditions.

DESCRIPTION OF THE INVENTION

[0002] The compounds according to the invention are compounds of generalformula (I)

[0003] wherein

[0004] A denotes a sulphur atom, oxygen atom, NH or N—C₁-C₄-alkyl,

[0005] R¹ denotes a group selected from among hydrogen, a C₁-C₆-alkylgroup optionally substituted by one or more halogen atoms, —SO₂H,—SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl, —O,phenyl-C₁-C₄-alkyl, —C₁-C₄-alkyl-NR⁷R⁸,

[0006] —C₁-C₄-alkyl-O—C₁-C₄-alkyl and C₃-C₆-cycloalkyl,

[0007] R², R⁹, which may be identical or different, denote a groupselected from among hydrogen, a C₁-C₆-alkyl group optionally substitutedby one or more halogen atoms, halogen, —NO₂, —SO₂H, —SO₂—C₁-C₆-alkyl,—SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl, —OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl,—C₁-C₄-alkyl-NR⁷R⁸ and —C₁-C₄-alkyl-O—C₁-C₄-alkyl, C₃-C₆-cycloalkyl, or

[0008] R¹ and R² together denote a C₂-C₆-alkylene bridge,

[0009] R⁷, R⁸, which may be identical or different, denote hydrogen orC₁-C₄-alkyl, and

[0010] R³, R⁴, R⁵, R⁶, which may be identical or different, denote agroup selected from among hydrogen, a C₁-C₆-alkyl group optionallysubstituted by one or more halogen atoms, phenyl-C₁-C₄-alkyl, halogen,—CN, —NO₂, —SO₂H, —SO₃H, —SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —SO₂—NR⁷R⁸,—COOH, —CO—C₁-C₆-alkyl, —O—CO—C₁-C₄-alkyl, —CO—O—C₁-C₄-alkyl, —CO—NR⁷R⁸,—OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl, —NR⁷R⁸ and an aryl group optionallymono- or polysubstituted by halogen atoms, —NO₂, —SO₂H or C₁-C₄-alkyl,

[0011] optionally in the form of the various enantiomers anddiastereomers thereof, as well as the pharmacologically acceptable saltsthereof.

[0012] Compounds of general formula (I) are preferred wherein

[0013] A denotes a sulphur atom, oxygen atom or N—C₁-C₂-alkyl,

[0014] R¹ denotes a group selected from among hydrogen, a C₁-C₆-alkylgroup optionally substituted by one or more halogen atoms, —SO₂H,—SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl, —O,—C₁-C₄-alkyl-NR⁷R⁸ and —C₁-C₄-alkyl—O—C₁-C₄-alkyl, benzyl,

[0015] R², R⁹, which may be identical or different, denote a groupselected from among hydrogen, a C₁-C₆-alkyl group optionally substitutedby one or more halogen atoms, halogen, —NO₂, —SO₂H, —SO₂—C₁-C₆-alkyl,—SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl, —OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl,—C₁-C₄-alkyl-NR⁷R⁸ and —C₁-C₄-alkyl-O—C₁-C₄-alkyl, or

[0016] R¹ and R² together denote a C₃-C₆-alkylene bridge, and

[0017] R³, R⁴, R⁵, R⁶, which may be identical or different, denote agroup selected from among hydrogen, a C₁-C₄-alkyl group optionallysubstituted by one or more halogen atoms, phenyl-C₁-C₄-alkyl, halogen,—CN, —NO₂, —SO₂H, —SO₃H, —SO₂CH₃, —SOCH₃, —CO—C₁-C₄-alkyl, —OH,—O—C₁-C₄-alkyl and —S—C₁-C₄-alkyl,

[0018] optionally in the form of the various enantiomers anddiastereomers thereof, as well as the pharmacologically acceptable saltsthereof.

[0019] Compounds of general formula (I) are particularly preferredwherein

[0020] A denotes a sulphur atom or N—C₁-C₂-alkyl,

[0021] R¹, R², R⁹, which may be identical or different, denote hydrogen,C₁-C₄-alkyl, benzyl or

[0022] R¹ and R² together denote a C₃-C₄-alkylene bridge, and R³, R⁴,R⁵, R6 , which may be identical or different, denote a group selectedfrom among hydrogen, C₁-C₄-alkyl, CF₃, NO₂, benzyl, —SO₂—C₁-C₄-alkyl,—SO₃H and halogen, preferably fluorine, chlorine, bromine, mostpreferably fluorine or chlorine, optionally in the form of the variousenantiomers and diastereomers thereof, as well as the pharmacologicallyacceptable salts thereof.

[0023] Also particularly preferred are compounds of general formula (I)wherein

[0024] A denotes a sulphur atom or N—CH₃,

[0025] R¹, R², R⁹ which may be identical or different, denote hydrogen,C₁-C₄-alkyl or

[0026] R¹ and R² together denote a C₃-C₄-alkylene bridge,

[0027] R³, R⁵, R⁶, which may be identical or different, denote a groupselected from among hydrogen, C₁-C₄-alkyl and halogen, preferablyfluorine, chlorine, bromine, most preferably fluorine or chlorine, and

[0028] R⁴ denotes hydrogen, halogen or C₁-C₄-alkyl,

[0029] optionally in the form of the various enantiomers anddiastereomers thereof, as well as the pharmacologically acceptable saltsthereof.

[0030] Of particular importance according to the invention are thecompounds of general formula (I) wherein

[0031] R¹ denotes methyl, ethyl, i-propyl, n-butyl or benzyl, optionallyin the form of the various enantiomers and diastereomers thereof, aswell as the pharmacologically acceptable salts thereof.

[0032] Particularly preferred are compounds of general formula (I),wherein

[0033] A denotes a sulphur atom,

[0034] R¹ denotes methyl,

[0035] R², R⁹ denote hydrogen,

[0036] R³ denotes a group selected from among hydrogen, methyl, CN andhalogen, preferably fluorine, chlorine, bromine, most preferablyfluorine or chlorine,

[0037] R⁵ denotes a group selected from among hydrogen, methyl andhalogen, preferably fluorine, chlorine, bromine, most preferablyfluorine or chlorine,

[0038] R⁴ denotes hydrogen, and

[0039] R⁶ denotes hydrogen or methyl, preferably hydrogen,

[0040] optionally in the form of the pharmacologically acceptable saltsthereof.

[0041] Most particularly preferred are compounds of general formula (I),wherein

[0042] A denotes a sulphur atom,

[0043] R¹ denotes methyl,

[0044] R³ denotes hydrogen, fluorine or chlorine, and

[0045] R², R⁴, R5, R6, R9 denote hydrogen,

[0046] optionally in the form of the pharmacologically acceptable saltsthereof.

[0047] The alkyl groups used, unless otherwise stated, are branched andunbranched alkyl groups having 1 to 6 carbon atoms, preferably I to 4carbon atoms. Examples include: methyl, ethyl, propyl, butyl, pentyl andhexyl. The groups methyl, ethyl, propyl or butyl may optionally also bereferred to by the abbreviations Me, Et, Prop or Bu. Unless otherwisestated, the definitions propyl, butyl, pentyl and hexyl also include allpossible isomeric forms of the groups in question. Thus, for example,propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec.butyl and tert.-butyl, etc.

[0048] In the abovementioned alkyl groups, one or more hydrogen atomsmay optionally be substituted by the halogen atoms fluorine, chlorine,bromine or iodine. The substituents fluorine and chlorine are preferred.The substituent fluorine is particularly preferred. If desired, all thehydrogen atoms of the alkyl group may be replaced.

[0049] The alkyl group mentioned in the group phenyl-C₁-C₄-alkyl may bein branched or unbranched form. Unless otherwise stated benzyl andphenylethyl are preferred phenyl-C₁-C₄-alkyl groups. Benzyl isparticularly preferred.

[0050] The C₂-C₆-alkylene bridge may, unless otherwise stated, bebranched and unbranched alkylene groups having 2 to 6 carbon atoms, forexample ethylene, propylene, methylethylene, dimethylmethylene,n-butylene, 1-methylpropylene, 2-methylpropylene, 1.1-dimethylethylene,1 .2-dimethylethylene etc. n-Propylene and n-butylene bridges areparticularly preferred.

[0051] The aryl group is an aromatic ring system having 6-10 carbonatoms, preferably phenyl. In the abovementioned aryl groups, one or morehydrogen atoms may optionally be substituted by halogen atoms, —NO₂,—SO₂H or —C₁-C₄-alkyl, preferably fluorine, chlorine, —NO₂, ethyl ormethyl, most preferably fluorine or methyl.

[0052] The term C₃-C₆-cycloalkyl denotes saturated cyclic hydrocarbongroups having 3-6 carbon atoms, for example cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

[0053] The term halogen, unless otherwise stated, refers to fluorine,chlorine, bromine and iodine, preferably fluorine, chlorine and bromine,most preferably fluorine and chlorine, most preferably fluorine.

[0054] As already mentioned, the compounds of formula (I) or the variousenantiomers and diastereomers thereof may be converted into the saltsthereof, particularly for pharmaceutical use, into the physiologicallyand pharmacologically acceptable salts thereof. These salts may on theone hand take the form of physiologically and pharmacologicallyacceptable acid addition salts of the compounds of formula (I) withinorganic or organic acids. On the other hand, the compound of formula(I) where R¹ is hydrogen may be converted by reaction with inorganicbases into physiologically and pharmacologically acceptable salts withalkali or alkaline earth metal cations as counter-ion. The acid additionsalts may be prepared, for example, using hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, methanesulphonic acid, aceticacid, fumaric acid, succinic acid, lactic acid, citric acid, tartaricacid or maleic acid. It is also possible to use mixtures of the aboveacids. For preparing the alkali and alkaline earth metal salts of thecompound of formula (I) wherein R¹ denotes hydrogen, it is preferable touse the alkali and alkaline earth metal hydroxides and hydrides, thehydroxides and hydrides of the alkali metals, especially sodium andpotassium, being preferred, while sodium and potassium hydroxide areparticularly preferred.

[0055] The compounds according to the invention may be prepared in amanner known per se. The following general methods of synthesis shown inDiagrams 1 and 2 below are meant to illustrate the invention withoutrestricting it to their content.

[0056] Method 1

[0057] Starting from a compound of formula (IV) a compound of formula(V) is prepared by sulphonation and subsequent chlorination. Thecompound of formula (VI) obtained after condensation with aminoaceticacid derivatives is cyclised by the addition of polyphosphoric acid tothe target compound (I). Commercially unobtainable compounds of formula(IV) are prepared beforehand by converting the compounds of formula (II)into the compounds of formula (III), wherein R^(\), R^(\\) which may beidentical or different denote C1-C6-alkyl or together denote a1,2-ethylene or 1,3-propylene group, and subsequently cyclising themunder the effect of strong acids.

[0058] The general preparation of the compounds according to theinvention as shown in Diagram 1 is hereinafter described in more detailwith reference to the benzothiophene derivatives (A=S). The process canbe carried out analogously with the corresponding indole or benzofuranderivatives:

[0059] Synthesis of the diethoxy-ethyl-thiophenols (III):

[0060] 10 mmol of the thiophenol (II) are dissolved in 2-100 ml,preferably 3-20 ml, most preferably 4 ml of an alcohol, particularlymethanol, and combined with 10-50 mmol, preferably 11-30 mmol, mostpreferably 12 mmol of an alkoxide solution, particularly a sodiumethoxide solution. After 20-120 min, preferably 30 min, 10-50 mmol,preferably 11-30 mmol, most preferably 12 mmol of bromoacetaldehydedialkylacetal are added and the solution is heated for 2-16 h,preferably 5 h, to 20-100° C., preferably 50-70° C. After evaporation ofthe solution the residue is divided between an organic solvent andwater, particularly taken up with 30 ml of ether and 30 ml of water. Thephases are separated and the aqueous phase is then extracted with ether.The combined organic extracts are dried over sodium sulphate andevaporated down in vacuo. The crude product is used in the next reactionwithout further purification.

[0061] Instead of the solvent methanol it is also possible to useethanol, tetrahydrofuran, toluene, benzene, dimethylformamide,trichloromethane, dichloromethane, acetone or ethyl acetate, instead ofthe sodium methoxide solution it is possible to use potassium hydroxide,potassium-tert. butoxide, lithium hydroxide, triethylamine, DBU(1,8-diazabicyclo[5.4.0]undec-7-ene), sodium hydride or potassiumcarbonate as the base.

[0062] Synthesis of the benzothiophenes (IV):

[0063] 10-100 ml, preferably 30 ml, of polyphosphoric acid and 10-250ml, preferably 40 ml, of chlorobenzene are taken at 140° C. and 10 mmolof the dialkoxy-ethyl-thiophenol (III) are added. After 2-16 h,preferably 5 h, stirring at 90-160° C., preferably 140° C., the phasesare separated and the inorganic phase is extracted with ether. Thecombined organic extracts are dried over Na₂SO₄ and evaporated down invacuo. The residue is purified by distillation.

[0064] Instead of the polyphosphoric acid it is possible to use amixture of phosphorus pentoxide/phosphoric acid and zinc chloride, whiletoluene or xylene may be used instead of chlorobenzene.

[0065] Sulphonation of the benzothiophenes (IV):

[0066] 10 mmol of the benzothiophene derivative (IV) are dissolved in2-100 ml, preferably 3-80 ml, most preferably 4 ml, of acetic anhydrideand 10 to 100 mmol, preferably 11-80 mmol, most preferably 11 mmol, ofconc. sulphuric acid are added dropwise at 0-50° C., preferably 5-20° C.After 2-16 h, preferably 5 h, stirring at 20-100° C., preferably 25 C°,the mixture is poured onto a saturated NaCl solution. The crystalsformed are suction filtered and dried.

[0067] Instead of acetic anhydride it is possible to use methylenechloride, diisopropylether, ethyl acetate, trichloromethane, toluene,benzene or 1,4-dioxane, while oleum, sulphur trioxide, chlorosulphatesor combinations thereof may be used instead of conc. sulphuric acid.

[0068] Synthesis of benzothiophene-3-sulphonic acid chlorides (V):

[0069] 10 mmol of benzothiophene-3-sulphonic acids are combinedsuccessively with 10 to 500 mmol, preferably 90 mmol, of phosphorusoxytrichloride and 8-50 mmol, preferably 10 mmol of phosphoruspentachloride and heated for 2-16 h, preferably 5 h, at 20-100° C.,preferably by refluxing. The reaction mixture is then evaporated down invacuo and ice water is added. After extraction with ether the combinedorganic extracts are dried with disodium sulphate and the solvent iseliminated in vacuo. The crude product obtained is used in the followingsteps without purification.

[0070] Instead of the mixture of phosphorus oxytrichloride/phosphoruspentachloride, it is also possible to use thionyl chloride, phosphoruspentachloride, a mixture of phosphoric acid/chlorine or phosgene. Thereaction may alternatively be carried out in the diluents ethyl acetate,water, acetonitrile, N,N-dimethylacetamide, sulpholane, DMF, hexane ordichloroethane.

[0071] Synthesis of the benzothiophene-3-sulphonyl-amino-acetic acids:

[0072] 10 mmol of the chlorosulphonyl-benzothiophenes, 10-100 mmol,preferably 11-30 mmol, most preferably 12 mmol, of aminoacetic acid and10-100 mmol, preferably 11-30 mmol, most preferably 12 mmol, of sodiumhydroxide are dissolved in 16 ml of water and 16 ml of toluene. Thereaction mixture is stirred for 2-16 h at 0-110° C., preferably at 65°C., then the phases are separated. The aqueous phase is acidified with2N hydrochloric acid and extracted with ethyl acetate. The combinedorganic extracts are dried over sodium sulphate and evaporated down invacuo. The residue is purified by chromatography. Instead of sodiumhydroxide it is possible to use triethylamine, potassium carbonate,sodium hydrogen carbonate or sodium hydride, while instead of toluene itis possible to use tetrahydrofuran, diethylether, dichloromethane,trichloromethane, dioxane, acetone, benzene, ethanol, methanol, ethylacetate or acetonitrile.

[0073] Cyclisation of benzothiophene-3-sulphonyl-amino-acetic acids(VI):

[0074] 10 mmol of the benzothiophene-3-sulphonyl-amino-acetic acids arecombined with 10-200 g, preferably 40 g, of polyphosphoric acid andstirred for 2-16 h, preferably 5 h, at 20-110° C., preferably 75-95° C.Then the reaction mixture is poured onto ice water and extracted withethyl acetate. The combined organic extracts are dried over disodiumsulphate and concentrated by evaporation. The residue is purified bychromatography.

[0075] Process 2

[0076] The compounds of formula (V) prepared as intermediate compoundsin process 1 are reacted with primary amines to form the compounds offormula (VII) and then cyclised by the addition of a compound of formulaR²R⁹C═O in the presence of strong acid to form the target compounds (I).

[0077] Paraformaldehyde, trioxane or formalin may be used to prepare thecompounds of formula (I) wherein R¹ and R² denote hydrogen, whilemethanesulphonic acid, trifluoroacetic acid, sulphuric acid, phosphoricacid or polyphosphoric acid may be used as strong acids.

[0078] The general preparation of the compounds according to theinvention as shown in Diagram 2 is described hereinafter with referenceto the benzothiophene derivatives (A═S). The process can be carried outanalogously with the corresponding indole or benzofuran derivatives.

[0079] Synthesis of the benzothiophene-sulphonamides (VII):

[0080] 10 mmol of the chloro-benzothiophene-sulphonic acids (V) arecombined with an alcoholic solution of the primary amine (10-1000 mmolin 5-200 ml, for example 200 mmol in 50 ml ethanol) and then heated for2-16 h, preferably 5 h at 0-100 C°, preferably by refluxing. Thereaction mixture is then evaporated down in vacuo and purified bychromatography.

[0081] Instead of the alcoholic solvent it is possible to use toluene,benzene, trichloromethane, dichloromethane, diethylether,tetrahydrofuran, water, acetonitrile, acetic anhydride, acetone,pyridine, dimethylsulphoxide, dimethylformamide, dioxane or hexane.

[0082] Cyclisation of the benzothiophene-sulphonamides (VII) into thetarget compounds (I):

[0083] 10 mmol of the benzothiophene-sulphonamides are dissolved in0-100 ml, preferably 20-80 ml, most preferably about 40 ml ofmethanesulphonic acid and combined with a solution of 3-50 mmol,preferably 4-30, most preferably 5 mmol of trioxane in 0-100 ml,preferably about 12 ml of trifluoroacetic acid. The reaction mixture isstirred for 2-16 h, preferably 5 h, at 20-100 C°, preferably 30-80° C.,most preferably 35° C. and then poured onto ice water. After extractionwith ether and drying of the combined organic extracts over Na₂SO₄ thesolution is concentrated by evaporation. The crude product is purifiedby chromatography.

[0084] Instead of trioxane it is possible to use paraformaldehyde orformalin, while instead of trifluoroacetic acid it is possible to useboron trifluoride*diethylether, acetic acid, polyphosphoric acid,phosphoric acid or sulphuric acid. Acetic anhydride or dichloromethanemay be used as possible solvents. The new compounds of general formula(I) may be synthesised analogously to the following examples ofsynthesis. However, these Examples are intended solely as examples ofprocedure to illustrate the invention, without restricting it to theircontent.

[0085] Synthesis of 4-methyl-4,5-dihydro-1,3-dithia-4-aza-acenaphthylene3,3-dioxide

EXAMPLE 1

[0086] Step 1: sodium-benzothiophene-3-sulphonate:

[0087] 20 g of benzothiophene are placed in 25 ml of acetic anhydride,cooled to 5° C., and 8.7 ml of conc. sulphuric acid are slowly addedthereto. After a reaction time of 2 hours at ambient temperature thesolution is poured onto 400 ml of ice water and then washed with 250 mlof diethylether. By the addition of NaCl the product is separated outfrom the aqueous solution, the white solid precipitated is suctionfiltered and dried in the drying cupboard at 60° C. Yield: 26 g.

[0088] Step 2: 3-Chlorosulphonyl-1-benzothiophene:

[0089] 180 g of sodium-benzothiophene-3-sulphonate are placed in 650 mlof phosphorus oxychloride and then combined with 156 g of phosphoruspentachloride. The reaction mixture is refluxed for 3.5 hours before theexcess phosphorus oxychloride is eliminated by distillation in vacuo.The residue is taken up in 800 ml of chloroform and the precipitateformed is separated off by filtering. The filtrate is concentrated byevaporation and stirred into 800 ml of petroleum ether with heating. Thecrystalline substance thus precipitated is filtered off, washed withpetroleum ether and dried at 35° C.

[0090] Yield: 113 g. M.p.: 88-89° C.

[0091] Step 3: [(benzothiophene-3-sulphonyl)-methyl-amino]-acetic acid:

[0092] 6 g of NaOH, 23.27 g of 3-chlorosulphonyl-benzothiophene and13.36 g of sarcosine are added to a mixture of 200 ml of toluene and 200ml of water and stirred for 6.5 hours at 60° C. For working up, theaqueous phase is separated off and the organic phase is extracted with100 ml of 2 N NaOH solution. The combined aqueous phases are acidifiedwith conc. HCl and then extracted twice with 300 ml of ethyl acetate.After washing with saturated aqueous saline solution and drying overmagnesium sulphate the organic phase is concentrated by evaporation. Thecrude product obtained is recrystallised from 100 ml of dichloroethane.Yield: 13.14 g. M.p.: 139-140° C.

[0093] Step 4: 4.5-Dihydro-4-methyl-3.3-dioxide-thieno[2,34-ij]j[2.3]benzothiazine:

[0094] 110 g polyphosphoric acid are combined with 10.5 g of[(benzothiophene-3-sulphonyl)-methyl-amino]-acetic acid and stirred for75 min at 70-75° C., whereupon there is a vigorous development of gas.The reaction mixture is stirred into 1l of warm water and extractedthree times with 250 ml of methylene chloride. The combined organicphases are washed with 300 ml of a 2 N NaOH solution and then dried overmagnesium sulphate. The residue remaining after evaporation is purifiedby chromatography. Yield: 3.8 g. M.p.: 149-150° C.

[0095] Synthesis of 4-ethyl-4.5-dihydro-1,3-dithia-4-aza-acenaphthylene3,3-dioxide

EXAMPLE 2

[0096] 1.90 g of N-ethyl-benzo[b]thiophene-3-sulphonamide are dissolvedin 25 ml methanesulphonic acid at 35° C. and combined with a solution of0.29 g of trioxane in 8 ml of trifluoroacetic acid. After 2.5 h stirringat ambient temperature the reaction mixture is poured onto 400 ml of icewater. The solid formed is separated off by filtration, washed with 200ml of water and then dissolved while hot in 400 ml ofethanol/isopropanol (1:1) and separated from solid residues by filteringagain. The residue remaining after the concentration of the filtrate ispurified by chromatography. Yield: 0.82 g. M.p.: 156° C.

[0097] Synthesis of8-chloro-4-methyl-4,5-dihydro-1,3-dithia-4-aza-acenaphthylene3,3-dioxide

EXAMPLE 3

[0098] 0.2 g of 7-chloro-benzo[b]thiophene-3-sulphonic acid-methylamideare dissolved in 3 ml of methanesulphonic acid at 35° C. and combinedwith a solution of 0.03 g of trioxane in 0.9 ml trifluoroacetic acid.After 2 h stirring at 35° C. the reaction mixture is poured onto 100 mlof ice water and the aqueous phase is extracted with ethyl acetate. Thecombined organic extracts are dried with Na₂SO₄, evaporated down invacuo and then purified by chromatography. Yield: 0.06 g. M.p.: 146° C.

[0099] Synthesis of6-fluoro-4-methyl-4,5-dihydro-1,3-dithia-4-aza-acenaphthylene3,3-dioxide

EXAMPLE 4

[0100] 0.37 g of 5-fluoro-benzo[b]thiophene-3-sulphonic acid-methylamideare dissolved in 5.9 ml of methanesulphonic acid at 35° C. and combinedwith a solution of 0.06 g of trioxane in 1.8 ml of trifluoroacetic acid.After 2.5 h stirring at 35° C. the reaction mixture is poured onto 100ml of ice water and the aqueous phase is extracted with ethyl acetate.The combined organic extracts are dried with Na₂SO₄, evaporated down invacuo and then purified by chromatography. Yield: 0.22 g. M.p.: 175° C.

[0101] Synthesis of6-chloro-4-methyl-4,5-dihydro-1.3-dithia-4-aza-acenaphthylene3.3-dioxide

EXAMPLE 5

[0102] 0.60 g of 5-chloro-benzo[b]thiophene-3-sulphonic acid-methylamideare dissolved in 8.9 ml of methanesulphonic acid at 35° C. and combinedwith a solution of 0.09 g trioxane in 2.7 ml trifluoroacetic acid. After3 h stirring at 35° C. the reaction mixture is poured onto 100 ml of icewater and the aqueous phase is extracted with ethyl acetate. Thecombined organic extracts are dried with Na₂SO4, evaporated down invacuo and then purified by chromatography. Yield: 0.30 g. M.p.: 196° C.

[0103] Synthesis of1,4-dimethyl-4,5-dihvdro-1H-3-thia-1,4-diaza-acenaphthylene 3.3-dioxide

EXAMPLE 15

[0104] 4 g of N,N′-dimethylindole-3-sulphonamide are dissolved in 100 mlmethanesulphonic acid at 35° C. and combined with 0.54 g of trioxane in25 ml trifluoroacetic acid. After 1 h stirring at 35° C. the reactionmixture is poured onto ice and the aqueous phase is extracted with ethylacetate. The combined organic extracts are dried with Na₂SO4, evaporateddown in vacuo and then purified by chromatography. Yield: 0.07 g. M.p.:190° C.

[0105]4-methyl-3,3-dioxo-4,5-dihydro-3H-1,3-dithia-4-aza-acenaphthylene-6-carbonitrile

EXAMPLE 16

[0106] 1 g of6-bromo-4-methyl-4,5-dihydro-1,3-dithia-4-aza-acenaphthylene-3,3-dioxide is added to 0.32 g of copper (I) cyanide and 10 ml ofpyridine. The reaction mixture is heated to 190° C. for 7 h, then pouredonto 10 ml of ammonia solution and combined with water and ether (30 mlof each). The aqueous phase is extracted with ether. The combinedorganic phases are washed with 10 ml of dilute hydrochloric acid andthen dried over Na₂SO₄. After the solution has been evaporated down invacuo it is purified by chromatography. Yield: 0.06 g. M.p. 238° C.

[0107] The following compounds of formula IA wherein Ph denotes phenylare obtained inter alia analogously to the process describedhereinbefore: TABLE 1 (IA)

M.p. Ex. R¹ R² R³ R⁴ R⁵ R⁶ A [° C.]  1 CH₃ H H H H H S  149- 150  2 C₂H₅H H H H H S 156  3 CH₃ H H H Cl H S 146  4 CH₃ H F H H H S 175  5 CH₃ HCl H H H S 196  6 CH₃ H H H H CH₃ S 208  7 CH₃ H CH₃ H H H S 187  8CH₂—Ph H H H H H S  74  9 i-C₃H₇ H H H H H S 117 10 CH₃ H H H CH₃ H S136 11 CH₃ H Br H H H S 203 12 n-C₄H₉ H H H H H S  91 13 CH₃ H Cl H Cl HS 164 14 —CH₂—CH₂— H H H H S 149 CH₂— 15 CH₃ H H H H H N—CH₃ 190 16 CH₃H CN H H H S 238 17 CH₃ H H H i-C₃H₇ H S 125 18 CH₃ H H H H H O 19 C₂H₅H H H H H O 20 CH₃ H H H Cl H O 21 CH₃ H F H H H O 22 CH₃ H Cl H H H O23 CH₃ H H F H H S 24 CH₃ H H H F H S 25 CH₃ H SO₃H H H H S 26 CH₃ H HSO₃H H H S 27 CH₃ H H H SO₃H H S 28 CH₃ H CF₃ H H H S 29 CH₃ H H CF₃ H HS 30 CH₃ H H H CF₃ H S 31 CH₃ H F H CF₃ H S 32 CH₃ H NO₂ H H H S 33 CH₃H H NO₂ H H S 34 CH₃ H H H NO₂ H S 35 CH₃ H F H NO₂ H S 36 CH₃ CH₃ H H HCH₃ S 37 H H H H H H S 38 H H F H H H S 39 H CH₃ H H H CH₃ S 40 C₂H₄— HH H H H S N(CH₃)₂ 41 CH₃ CF₃ H H H H S 42 CH₃ F H H H H S 43 CH₃ H H H HCO₂C₂H₄ S 44 CH₃ Ph H H H H S 45 CH₃ H Ph H H H S 46 CH₃ H H H Ph H S 47CH₃ H OH H H H S 48 CH₃ H H H OH H S 49 CH₃ H H OCH₃ H H S 50 CH₃ HN(CH₃)₂ H H H S 51 CH₃ H F H N(CH₃)₂ H S 52 CH₃ H F F F H S

[0108] It has been found that the compounds of general formula (I) arecharacterised by their great wide range of applications in thetherapeutic field. Particular mention should be made of thoseapplications in which the positive modulation of AMPA receptors plays apart. The effect of the compounds according to the invention as AMPAreceptor modulators was measured electrophysiologically on cells whichexpress functional AMPA receptors. Investigations were carried out tosee whether the test substances have a positive allosteric influence onthe agonist-induced current.

[0109] The test was carried out at concentrations of between 0.3 μmoland 300 μmol. TABLE 2 Intensification of the agonist-induced current (+good, ++ very good activity) Example Effectiveness 1 ++ 2 + 3 + 4 ++ 5 +

[0110] The new compounds can also be used to treat illnesses orconditions in which neuronal networks which require AMPA receptors inorder to function are damaged or limited in their function.

[0111] The compounds of general formula (I) can thus be used indementias, in neurodegenerative or psychotic illnesses and inneurodegenerative disorders and cerebral ischaemias of various origins,preferably in schizophrenia or learning and memory disorders.

[0112] The following are also included: epilepsy, hypoglycaemia,hypoxia, anoxia, cerebral trauma, brain oedema, amyotropic lateralsclerosis, Huntington's Disease, Alzheimer's disease, sexualdysfunction, disorders of sensory/motor function, memory formation,hyperkinetic behavioural changes (particularly in children),hypotension, cardiac infarct, cerebral pressure (increased intracranialpressure), ischaemic and haemorrhagic stroke, global cerebral ischaemiaon stoppage of the heart, acute and chronic neuropathic pain, diabeticpolyneuropathy, tinnitus, perinatal asphyxia, psychoses, Parkinson'sdisease and depression, and related anxiety states.

[0113] The new compounds may also be given in conjunction with otheractive substances, such as those used for the same indications, or forexample with neuroleptics, nootropics, psychostimulants, etc. They maybe administered topically, orally, transdernally, nasally, parenterallyor by inhalation. Moreover, the compounds of general formula I or thesalts thereof may also be combined with active substances of otherkinds.

[0114] The compounds of general formula (I) may be given on their own orin conjunction with other active substances according to the invention,and possibly also in conjunction with other pharmacologically activesubstances. Suitable preparations include for example tablets, capsules,suppositories, solutions,—particularly solutions for injection (s.c.,i.v., i.m.) and infusion—elixirs, emulsions or dispersible powders. Thecontent of the pharmaceutically active compound(s) should be in therange from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of thecomposition as a whole, i.e. in amounts which are sufficient to achievethe dosage range specified below.

[0115] Suitable tablets may be obtained, for example, by mixing theactive substance(s) with known excipients, for example inert diluentssuch as calcium carbonate, calcium phosphate or lactose, disintegrantssuch as corn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

[0116] Coated tablets may be prepared accordingly by coating coresproduced analogously to the tablets with substances normally used fortablet coatings, for example collidone or shellac, gum arabic, talc,titanium dioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number or layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

[0117] Syrups or elixirs containing the active substances orcombinations thereof according to the invention may additionally containa sweetener such as saccharine, cyclamate, glycerol or sugar and aflavour enhancer, e.g. a flavouring such as vanilline or orange extract.They may also contain suspension adjuvants or thickeners such as sodiumcarboxymethyl cellulose, wetting agents such as, for example,condensation products of fatty alcohols with ethylene oxide, orpreservatives such as p-hydroxybenzoates.

[0118] Solutions for injection and infusion are prepared in the usualway, e.g. with the addition of isotonic agents, preservatives such asp-hydroxybenzoates, or stabilisers such as alkali metal salts ofethylenediamine tetraacetic acid, optionally using emulsifiers and/ordispersants, whilst if water is used as the diluent, for example,organic solvents may optionally be used as solvating agents ordissolving aids, and transferred into injection vials or ampoules orinfusion bottles.

[0119] Capsules containing one or more active substances or combinationsof active substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

[0120] Suitable suppositories may be made for example by mixing withcarriers provided for this purpose, such as neutral fats orpolyethyleneglycol or the derivatives thereof. Excipients which may beused include, for example, water, pharmaceutically acceptable organicsolvents such as paraffins (e.g. petroleum fractions), vegetable oils(e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g.ethanol or glycerol), carriers such as e.g. natural mineral powders(e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g.highly dispersed silicic acid and silicates), sugars (e.g. cane sugar,lactose and glucose) emulsifiers (e.g. lignin, spent sulphite liquors,methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g.magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

[0121] The preparations are administered by the usual methods,preferably by oral or transdermal route, particularly orally. For oraladministration the tablets may of course contain, apart from theabovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

[0122] For parenteral use, solutions of the active substances withsuitable liquid carriers may be used.

[0123] The dosage for intravenous use is from 1-1000 mg per hour,preferably between 5 and 500 mg per hour.

[0124] However, it may sometimes be necessary to depart from the amountsspecified, depending on the body weight, the route of administration,the individual response to the drug, the nature of its formulation andthe time or interval over which the drug is administered. Thus, in somecases it may be sufficient to use less than the minimum dose givenabove, whereas in other cases the upper limit may have to be exceeded.When administering large amounts it may be advisable to divide them upinto a number of smaller doses spread over the day.

[0125] The following examples of formulations illustrate the presentinvention without restricting its scope:

Examples of Pharmaceutical Formulations

[0126] A) Tablets per Tablet active substance 100 mg lactose 140 mgmaize starch 240 mg polyvinylpyrrolidone  15 mg magnesium stearate  5 mg500 mg

[0127] The finely-ground active substance, lactose and some of the maizestarch are mixed together. The mixture is screened, then moistened witha solution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining maize starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size. B) Tablets per Tablet activesubstance  80 mg lactose  55 mg maize starch 190 mg microcrystallinecellulose  35 mg polyvinylpyrrolidone  15 mg sodium-carboxymethyl starch 23 mg magnesium stearate  2 mg 400 mg

[0128] The finely ground active substance, some of the corn starch,lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixedtogether, the mixture is screened and worked with the remaining cornstarch and water to form a granulate which is dried and screened. Thesodiumcarboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize. C) Ampoule solution active substance 50 mg sodium chloride 50 mgaqua for inj.  5 ml

[0129] The active substance is dissolved in water at its own pH oroptionally at pH 5.5 to 6.5 and sodium chloride is added to make itisotonic. The solution obtained is filtered free from pyrogens and thefiltrate is transferred under aseptic conditions into ampoules which arethen sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mgand 50 mg of active substance.

What is claimed is:
 1. A compound of the formula (I)

wherein: A denotes a sulphur atom, oxygen atom, >NH or >N—C₁-C₄-alkyl;R¹ denotes a group selected from among hydrogen, C₁-C₆-alkyl optionallysubstituted by one or more halogen atoms, —SO₂H, —SO₂—C₁-C6-alkyl,—SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl, O⁻, C₁-C₄-alkyl substituted by aphenyl, —C₁-C₄-alkyl-NR⁷R⁸, —C₁-C₄-alkyl-O—C₁-C₄-alkyl and,—C₃-C₆-cycloalkyl; R²and R⁹ are identical or different and each denotesa group selected from among hydrogen, C₁-C₆-alkyl optionally substitutedby one or more halogen atoms, halogen, —NO₂, —SO₂H, —SO₂—C₁-C₆-alkyl,—SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl, —OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl,—C₁-C₄-alkyl-NR⁷R⁸, —C₁-C₄-alkyl-O—C₁-C₄-alkyl and —C₃-C₆-cycloalkyl;or, R¹ and R² together denote a C₂-C₆-alkylene bridge; R⁷ and R⁸ areidentical or different and each denotes hydrogen or C₁-C₄-alkyl; and,R³, R⁴, R⁵ and R⁶ are identical or different and each denotes a groupselected from among hydrogen, C₁-C₆-alkyl optionally substituted by oneor more halogen atoms, C₁-C₄-alkyl substituted by a phenyl, halogen,—CN, —NO₂, —SO₂H, —SO₃H, —SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl, —SO₂—NR⁷R⁸,—COOH, —CO—C₁-C₆-alkyl, —O—CO—C₁-C₄-alkyl, —CO—O—C₁-C₄-alkyl, —CO—NR⁷R⁸,—OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl, —NR⁷R⁸ and aryl (wherein said arylis optionally mono- or polysubstituted by halogen, —NO₂, —SO₂H orC₁-C₄-alkyl); or a pharmacologically acceptable salt thereof.
 2. Acompound of the formula (I) according to claim 1, wherein: A denotes asulphur atom, oxygen atom or >N—C₁-C₂-alkyl; R¹ denotes a group selectedfrom among hydrogen, C₁-C₆-alkyl optionally substituted by one or morehalogen atoms, —SO₂H, —SO₂—C₁-C₆-alkyl, —SO—C₁-C₆-alkyl,—CO—C₁-C₆-alkyl, —O⁻, —C₁-C₄-alkyl-NR⁷R⁸, —C₁-C₄-alkyl-O—C₁-C₄-alkyl andbenzyl; R², R⁹ which are identical or different and each denotes a groupselected from among hydrogen, C₁-C₆-alkyl optionally substituted by oneor more halogen atoms, halogen, —NO₂, —SO₂H, —SO₂—C₁-C6-alkyl,—SO—C₁-C₆-alkyl, —CO—C₁-C₆-alkyl, —OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl,—C₁-C₄-alkyl-NR⁷R⁸ and —C₁-C₄-alkyl-O—C₁-C₄-alkyl; or, R¹ and R²together denote a C₃-C₆-alkylene bridge; and, R³, R⁴, R⁵, R⁶ areidentical or different and each denotes a group selected from amonghydrogen, C₁-C₄-alkyl optionally substituted by one or more halogenatoms, C₁-C₄-alkyl substituted by a phenyl, halogen, —CN, —NO₂, —SO₂H,—SO₃H, —SO₂CH₃, —SOCH₃, —CO—C₁-C₄-alkyl, —OH, —O—C₁-C₄-alkyl and—S—C₁-C₄-alkyl; or a pharmacologically acceptable salt thereof.
 3. Acompound of general formula (I) according to claim 1, wherein: A denotesa sulphur atom or >N—C₁-C₂-alkyl; R¹, R², R9 are identical or differentand each denotes hydrogen, C₁-C₄-alkyl or benzyl; or, R¹ and R² togetherdenote a C₃-C₄-alkylene bridge; and R³, R⁴, R⁵, R⁶ are identical ordifferent and each denotes a group selected from among hydrogen,C₁-C₄-alkyl, CF₃, NO₂, benzyl, -SO₂-Cl-C₄-alkyl, —SO₃H and halogen; or apharmacologically acceptable salt thereof.
 4. A compound of the formula(I) according to claim 1, wherein: A denotes a sulphur atom or >N—CH₃;R¹, R², R⁹ are identical or different and each denotes hydrogen orC₁-C₄-alkyl; or, R¹ and R² together denote a C₃-C₄-alkylene bridge; R³,R⁵, R⁶ are identical or different and each denotes a group selected fromamong hydrogen, C₁-C₄-alkyl and halogen; and, R⁴ denotes hydrogen,halogen or C₁-C₄-alkyl; or a pharmacologically acceptable salt thereof.5. A compound of the formula (I) according to claim 4, wherein: R¹denotes methyl, ethyl, i-propyl, n-butyl or benzyl; or apharmacologically acceptable salt thereof.
 6. A compound of the formula(I) according to claim 1, wherein: A is a sulphur atom; R¹ is methyl; R²and R⁹ are both hydrogen; R³ is hydrogen, methyl, CN or halogen; R⁵ ishydrogen, methyl or halogen; R⁴ is hydrogen; and, R⁶ is hydrogen ormethyl; or a pharmacologically acceptable salt thereof.
 7. A compound ofgeneral formula (I) according to claim 1, wherein: A is a sulphur atom;R¹ is methyl; R³ is hydrogen, fluorine or chlorine; and, R², R⁴, R⁵,R⁶and R⁹ are each hydrogen; or a pharmacologically acceptablesaltsthereof.
 8. A method of treating cerebral ischaemia which methodcomprises administering to a host in need of such treatment atherapeutic amount of a compound of the Formula I in accordance withclaim 1, 2, 3, 4, 5, 6 or
 7. 9. A method of treating schizophrenia whichmethod comprises administering to a host in need of such treatment atherapeutic amount of a compound of the Formula I in accordance withclaim 1, 2, 3, 4, 5, 6 or
 7. 10. A method of treating impaired memorywhich method comprises administering to a host in need of such treatmenta therapeutic amount of a compound of the Formula I in accordance withclaim 1, 2, 3, 4, 5, 6 or
 7. 11. A method of treating an illnesses orcondition in which neuronal networks which require AMPA receptors inorder to function are damaged or limited in their function, which methodcomprises administering to a host in need of such treatment atherapeutic amount of a compound of the Formula I in accordance withclaim 1, 2, 3, 4, 5, 6 or
 7. 12. A method of treating Alzheimer'sdisease, which method comprises administering to a host in need of suchtreatment a therapeutic amount of a compound of the Formula I inaccordance with claim 1, 2, 3, 4, 5, 6 or
 7. 13. A pharmaceuticalcomposition comprising a compound of the Formula I in accordance withclaim 1, 2, 3, 4, 5, 6 or 7 and a pharmaceutically acceptable carrier.